The FDA first approved alogliptin in January 2013 for the indication of improving glycemic control in adults with type 2 diabetes mellitus (T2DM). It is a dipeptidyl peptidase-4 (DPP-4) inhibitor used to improve glycemic control in conjunction with diet and exercise.
T2DM is a chronic illness that is becoming a common diagnosis among American children and adults. According to the CDC, in 2015, approximately 100 million US adults had either diabetes or prediabetes. It is the seventh leading cause of death and also has a 2- to 4-fold increase in cardiovascular disease. The need for intensive glucose control is great, and the American Diabetes Association (ADA) currently recommends a hemoglobin A1C target of less than 7% in most nonpregnant patients, though some subsets of patients may have a more strict goal of less than 6.5%, while other subsets of patients may have a less stringent goal of less than 8%.
The ADAs Standards of Care currently consider DPP-4 inhibitors as add-on therapy if patients do not meet their A1C goal after three months of lifestyle modifications and metformin. DPP-4 inhibitors are a useful component of both dual and triple therapy. It is worth noting that current recommendations suggest selecting a second agent (after metformin) based on the patient’s atherosclerotic cardiovascular disease (ASCVD) risk status. If they have ASCVD, the clinician should choose an agent proven to reduce cardiovascular (CV) risks and mortality. Alogliptin has not shown to reduce CV risks or CV mortality; in fact, there are concerns about a potential risk of heart failure associated with DPP-4 inhibitors. Approximately half of all patients with T2DM will develop heart failure during their life, so this is a significant concern.
The EXAMINE trial was a multicenter, randomized, double-blind study that assessed alogliptin versus placebo (in addition to standard of care) in 5380 patients with a recent acute coronary syndrome event. This trial showed that alogliptin improved glycemic control and did not increase the risk of hypoglycemia, which was associated with a risk of major adverse cardiovascular outcomes. A study of the same patients in the EXAMINE trial found that in patients with T2DM and recent acute coronary syndromes, alogliptin did not increase the risk of heart failure. However, the SAVOR-TIMI 53 study showed that patients treated with saxagliptin (also a DPP-4 inhibitor) were more likely to be hospitalized for heart failure than those given placebo. DPP-4 use and heart failure is an ongoing area of research due to mixed results from current trials.
Incretin therapies (including DPP-4 inhibitors) are targets of research in type 1 diabetes mellitus (T1DM) due to their preserving effects on beta-cell mass. They currently do not have an approved indication for the treatment of T1DM.
DPP-4 is an abundant enzyme that is present on the surface of most cells. It rapidly deactivates some incretin hormones, such as a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). These hormones are both released by intestinal cells in response to a meal. By antagonizing DPP-4, active postprandial incretin levels can be prolonged, which can result in increased insulin synthesis and release and decreased glucagon secretion, all of which can help regulate glucose homeostasis.
Alogliptin is available as a 6.25 mg, 12.5 mg, and 25 mg oral tablet that is taken once daily without regard to food. In patients that are also taking insulin and/or secretagogues (i.e., sulfonylureas, meglitinides), a reduced dose of insulin or the secretagogue may be necessary. No dosage adjustment is necessary for patients with mild renal impairment 9creatinine clearance [CrCl] greater than 60 mL/min); however, the total daily dose should be reduced to 12.5 mg once daily if CrCl is between 30 to 60 mL/min, and further reduced to 6.25 mg once daily if CrCl is between 15 to 30 mL/min. For patients with CrCl less than 15 mL/min or in patients requiring hemodialysis, the dose should be reduced to 6.25 mg daily, and administration can be without regard to the timing of hemodialysis. There are no recommendations for adjusting the dose in patients with hepatic impairment.
There are also formulations of alogliptin in combination with metformin and pioglitazone. Alogliptin-metformin is available in strengths of 12.5-500 mg, and 12.5-1000 mg and dosing is twice daily. Alogliptin-pioglitazone is available in strengths of 12.5-15 mg, 12.5-30 mg, 12.5-45 mg, 25-15 mg, 25-30 mg, and 25-45 mg and is taken once daily.
According to the package insert, there are reports of serious hypersensitivity reactions with alogliptin. These reactions include anaphylaxis, angioedema, and cutaneous reactions and are rare. More common reactions include nasopharyngitis, which occurred in 4.4% of patients, while a headache and upper respiratory tract infection both occurred in 4.2% of patients. Renal function abnormalities appeared to occur more often in patients with high CV risk (3% without CV risk versus 23% with CV risk).
One concern related to adverse events includes arthralgias. The FDA cautioned in 2015 that treatment with DPP-4 inhibitors might cause serious arthralgias. In a meta-analysis published in 2017 evaluating 67 randomized controlled trials, there was a suggestion of significantly increased risk of overall arthralgia (p = 0.003), but a non-significant increase in serious arthralgias (p = 0.20). The benefits of glycemic control versus the risk of arthralgia should be a factor when prescribing DPP-4 inhibitors, including alogliptin.
Bullous pemphigoid (a cutaneous autoimmune blistering disorder) is also a reported side effect with DPP-4 inhibitor use. After discontinuation of the offending drug and topical or immunosuppressive therapy, cases have typically resolved. If patients develop blisters, they should be advised to stop the DPP-4 inhibitor and seek care with a dermatologist.
Baseline liver function tests are a recommendation because reports exist of cases of fatal and nonfatal hepatic failure in postmarketing surveillance. Ruling out underlying liver disease may be warranted.
There are case reports of pancreatitis, and alogliptin should be discontinued immediately if pancreatitis is suspected.
Alogliptin is contraindicated in patients with a history of hypersensitivity to the drug or any component of the formulation.
Patients taking alogliptin should have their A1C monitored every three months if their A1c is not at goal and every six months if they are meeting their goal. Serum glucose, renal function, and baseline liver function tests (as indicated) also should be monitored. Patients also should be monitored for signs and symptoms of heart failure, pancreatitis, and dermatologic or allergic reactions.
In clinical trials, doses of 800 mg to healthy participants and participants with T2DM received doses of 400 mg. No serious adverse effects occurred with these high doses.
Healthcare workers, including nurse practitioners who prescribe alogliptin for type 2 diabetes, should also educate the patient on the importance of changes in lifestyle, diet, and exercise. Nursing can play a crucial role in this aspect of care, particularly a nurse certified as a diabetes educator. The pharmacist should also have input into the regimen, checking for interactions, noting the appropriateness and synergy of the agents chosen, and offering counsel to the patient on dosing and administration. At the same time, serum glucose, renal function, and baseline liver function tests (as indicated) also should be monitored. Patients also should be monitored for signs and symptoms of heart failure, pancreatitis, and dermatologic or allergic reactions, which is another area where nursing will make a significant contribution. All providers, the clinician, pharmacist, and nursing, need to exercise open collaboration and communication as an interprofessional team when a patient is receiving therapy with alogliptin to direct the case towards optimal outcomes. [Level V]
|||Smyth B,Perkovic V, New hypoglycemic agents and the kidney: what do the major trials tell us? F1000Research. 2018; [PubMed PMID: 30542615]|
|||Cheng JWM,Colucci VJ,Kalus JS,Spinler SA, Managing Diabetes and Preventing Heart Disease: Have We Found a Safe and Effective Agent? The Annals of pharmacotherapy. 2018 Dec 5; [PubMed PMID: 30516068]|
|||Zhu B,Li Y,Mei W,He M,Ding Y,Meng B,Zhao H,Xiang G, Alogliptin improves endothelial function by promoting autophagy in perivascular adipose tissue of obese mice through a GLP-1-dependent mechanism. Vascular pharmacology. 2018 Nov 14; [PubMed PMID: 30447331]|
|||Sano M, Mechanism by which dipeptidyl peptidase-4 inhibitors increase the risk of heart failure and possible differences in heart failure risk. Journal of cardiology. 2019 Jan; [PubMed PMID: 30318179]|
|||Ling J,Cheng P,Ge L,Zhang DH,Shi AC,Tian JH,Chen YJ,Li XX,Zhang JY,Yang KH, The efficacy and safety of dipeptidyl peptidase-4 inhibitors for type 2 diabetes: a Bayesian network meta-analysis of 58 randomized controlled trials. Acta diabetologica. 2018 Sep 21; [PubMed PMID: 30242726]|
|||Bowes CD,Lien LF,Butler J, Treatment of Diabetes in Patients with Heart Failure. Current cardiology reports. 2018 Aug 27; [PubMed PMID: 30151728]|
|||Gomez-Peralta F,Abreu C,Gomez-Rodriguez S,Barranco RJ,Umpierrez GE, Safety and Efficacy of DPP4 Inhibitor and Basal Insulin in Type 2 Diabetes: An Updated Review and Challenging Clinical Scenarios. Diabetes therapy : research, treatment and education of diabetes and related disorders. 2018 Oct; [PubMed PMID: 30117055]|
|||Alogliptin 2006; [PubMed PMID: 29999685]|